1. Field of the Invention
The present invention relates to a new hepatotoxicity-free pharmaceutical composition containing acetaminophen (APAP), in particular, a new pharmaceutical composition that contains a combination of acetaminophen and one or any combinations of common and pharmaceutically acceptable excipients that can inhibit the activity of P450 2E1 (CYP2E1) to reduce hepatotoxicity induced by acetaminophen.
2. Description of the Prior Art
Acetaminophen (also known as Panadol) is also called paracetamol or N-acetyl-para-aminophenol (APAP) and is the most widely used pain-relieving and fever-reducing drug on the market. Each year, numerous cases of drug intoxication or suicide are reported due to improper use of APAP, and liver damage caused by APAP is the main cause of severe diseases and death. A number of clinical studies have demonstrated that hepatotoxicity induced by APAP is preventable and early diagnosis along with real-time administration of the antidote N-acetylcysteine (NAC) can effectively prevent the occurrence of hepatotoxicity.
Early detection of acetaminophen overdose is necessary because the best prognosis can be achieved if the antidote is given within 8 hours after poisoning. The early signs of drug intoxication include discomfort, nausea and vomiting. However, some patients may show no signs of intoxication at the early stage (stage 1) even if their blood concentrations of acetaminophen are at the poisoning levels and their abnormal liver function is apparently abnormal. The signs of hepatotoxicity, such as abdominal pain, persistent vomiting, jaundice, right upper quadrant pain, usually become apparent 24-48 hours after ingestion of a significant amount of acetaminophen (stage 2). Serum amintransferase usually starts to rise 16 hours after administration with clinical symptoms. Stage 3 usually occurs 3-4 days after administration and the degree of liver damage as well as prognosis can be well predicted at the time. The signs of hepatotoxicity progress from mild symptoms with elevated liver function values (AST>1,000 IU/L) to severe acute fulminant hepatitis accompanied by metabolic acidosis, jaundice, hyperglycemia, AST>1,000 IU/L, abnormal blood clotting and hepatic/brain lesions. Stage 4 will cause oliguria renal failure or death in severe cases.
Some patients with acetaminophen intoxication show only mild liver damage but with severe renal toxicity which is mainly caused by direct metabolism of APAP in P-450s (cytochrome P450s, CYPs) of the renal tubule. Nonetheless, acute renal failure may also result from hepatorenal syndrome caused by acute liver failure and the fraction excretion of Na (FeNa) can be used for differentiation primary renal damage (FeNa>1) from hepatorenal syndrome (FeNa>1). The calculation formula for FeNa is (Sodiumurinary÷Creatinineurinary)÷(Sodiumplasma÷Creatinineplasma)×100.
The peak concentration of acetaminophen in blood is achieved 1-2 hours after oral administration and a significant amount is eliminated by liver, more than 90% is conjugated to glucuronide and sulfate and form non-toxic metabolites and only less than 5% is eliminated by different CYPs, including CYP2E1, CYP1A2 and CYP3A4, and among which CYP2E1 and CYP1A2 are the major enzymes for metabolism. The metabolite produced by these enzymes, N-acetyl-p-benzoquinoneimine (NAPQI, as shown in FIG. 1) is a very active electrophile. Under normal conditions, NAPQI will react immediately with glutathione in the cell and form non-toxic mercaptide. Overdose of acetaminophen makes the consumption rate of glutathione greater than its synthesis rate and when the glutathione level of the cell is lower than the normal range of 30%, NAPQI will bind to large molecules or nucleic acids containing cysteine and lead to liver damage. From histochemical stains, NAPQI will bind to the thiol group of cysteine and form a covalent bond in centrilobular areas before occurrence of liver cell necrosis.
Patients with liver disease, alcohol addiction or who are taking drugs which may induce the activity of P450 such as Carbamazepine, Ethanol, Isoniazid, Phenobarbital (may be other barbiturates), Phenytoin, Sulfinpyrazone, Sulfonylureas, Rifampin and Primidone are the susceptible groups of developing severe hepatotoxicity caused by APAP and may easily die if the patient also develops complications such as adult respiratory distress syndrome, cerebral edema, uncontrollable bleeding, infection or Multiple organ dysfunction syndrome (MODS). Take alcohol for example, alcohol is mainly eliminated by CYP2E1 of liver and its mechanism of APAP intoxication is divided into three stages: at the first stage alcohol competes the receptors for CYP2E1 with APAP in the liver and the concentration of NAPQI will reduce during the stage, at the second stage alcohol prolongs the half life of CYP2E1 from 7 hours to 37 hours which increases the level of CYP2E1 in the liver and the concentration of NAPQ1 will is slowly increase during this stage, and at the third stage, during alcohol withdrawal, more CYP2E1 is found in the liver to eliminate acetaminophen and consequently the toxic metabolites of acetaminophen increases significantly and lead to liver damage. Recent studies have shown that diallyl sulfide can effectively prevent hepatotoxicity caused by acetaminophen in mice and further demonstrated diallyl sulfide can inhibit the activity of CYP2E1. It is speculated that the protection mechanism of diallyl sulfide against hepatotoxicity induced by acetaminophen is by inhibition of the production of the intermediate NAPQI from acetaminophen.
Use of invasive and non-invasive methods to investigate the liver function of rats so as to monitor progress of liver damage and screen for liver diseases. The most common methods used include measurement of the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, liver cell products such as bilirubin and albumin as well as coagulation factors by prothrombin time prior to testing. Quantitative liver function is measured based on the serum concentrations of the substrates that almost exclusively processed in the liver. Elimination of these substrates is determined according to the blood flow of the hepatic portal vein and artery and the effects of liver cells on these substrates. Liver blood flow is associated with the levels of the substrates of liver; on the contrary, elimination of the substrate depends on the metabolic capacity in liver.
Galactose is a saccharine that has a high extraction ratio and 90% is eliminated by liver. In liver, galactose is converted into glucose-1-phosphate by galactokinase through a process called epimerization. The reaction of galactokinase is the rate-limiting step of galactose metabolism in liver cells. The high extraction rate of galactose makes metabolism of galactose which depends on liver blood flow and liver function the most important method for assessing liver function. At present, no definite rules are available for assessing residual liver function of rats. Measurement of the metabolic capacity of a definite compound (e.g. galactose) can help prediction of the rate-limiting step of a certain metabolic pathway and provide the representative values of residual liver function.
The inventor of present invention examined the patients with chronic hepatitis, cirrhosis and liver cancer by using galactase single point (GSP) and the result indicates GSP can accurately identify these liver diseases. GSP has been successfully applied to measurement of elimination in patients with liver disease, for example, the residual liver function of promazine and cefoperazone. In addition, GSP has become one of the methods for testing liver function recommended by the U.S. FDA in the Guidance for Industry.
In summary, a number of defects remain in the uses of acetaminophen.